This invention relates to a group of novel phosphites and nucleoside-3'-phosphite derivatives useful for synthesis of oligonucleotides and to the synthesis of oligonucleotides using the novel nucleoside-3'-phosphites.
For the chemical synthesis of oligonucleotides the phosphoramidite approach is well known. However, this approach has disadvantages in several respects. In the synthesis of the phosphoramidite unit it is necessary to use chlorophosphine or a phosphitilating agent of bisamide type using an expensive azole. Both chlorophosphine and the obtained phosphoramidite unit are unstable. In the multi-step process an oxidation reaction is needed at each step. After the oligonucleotide synthesizing process there is the need of another reaction for eliminating the phosphate protecting group from the product.
The disadvantages of the phosphoramidite approach are obviated by the H-phosphonate approach. In this method the H-phosphonate unit is stable, and the reaction time is shorter than in the phosphoramidite approach. It is unnecesary to use a phosphate protecting group, and the process includes only one oxidation reaction which is carried out after completion of the condensation reaction.
However, there are still some problems about the H-phosphonate approach such as the unstableness of pivaloyl chloride used as a condensing agent in the condensation reaction, formation of hydrochlorides during the reaction and lack of a good phosphonylating agent for the phosphonate unit.